Tryptophol Acetate and Tyrosol Acetate, Small-Molecule Metabolites Identified in a Probiotic Mixture, Inhibit Hyperinflammation

Orit Malka, Ravit Malishev, Marina Bersudsky, Manikandan Rajendran, Mathumathi Krishnamohan, Jakeer Shaik, Daniel A. Chamovitz, Evgeni Tikhonov, Eliya Sultan, Omry Koren, Ron N. Apte, Benyamin Rosental, Elena Voronov, Raz Jelinek

Research output: Contribution to journalArticlepeer-review

Abstract

Probiotic fermented foods are perceived as contributing to human health; however, solid evidence for their presumptive therapeutic systemic benefits is generally lacking. Here we report that tryptophol acetate and tyrosol acetate, small-molecule metabolites secreted by the probiotic milk-fermented yeast Kluyveromyces marxianus, inhibit hyperinflammation (e.g., "cytokine storm"). Comprehensive in vivo and in vitro analyses, employing LPS-induced hyperinflammation models, reveal dramatic effects of the molecules, added in tandem, on mice morbidity, laboratory parameters, and mortality. Specifically, we observed attenuated levels of the proinflammatory cytokines IL-6, IL-1α, IL-1β, and TNF-α and reduced reactive oxygen species. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress proinflammatory cytokine generation, rather brought their concentrations back to baseline levels, thus maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, leading to NF-kB inhibition. Overall, this work illuminates phenomenological and molecular details underscoring anti-inflammatory properties of small molecules identified in a probiotic mixture, pointing to potential therapeutic avenues against severe inflammation.

Original languageEnglish
Pages (from-to)531-547
Number of pages17
JournalJournal of Innate Immunity
Volume15
Issue number1
DOIs
StatePublished - 21 Feb 2023

Bibliographical note

Publisher Copyright:
© 2023 S. Karger AG. All rights reserved.

Keywords

  • Anti-inflammation
  • Catechol metabolites
  • Fermented foods
  • Hyperinflammation
  • Probiotics

Fingerprint

Dive into the research topics of 'Tryptophol Acetate and Tyrosol Acetate, Small-Molecule Metabolites Identified in a Probiotic Mixture, Inhibit Hyperinflammation'. Together they form a unique fingerprint.

Cite this